Prevention of Symptomatic Skeletal Events With Denosumab Administered Every 4 Weeks Versus Every 12 Weeks
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ClinicalTrials.gov Identifier: NCT02051218 |
Recruitment Status :
Active, not recruiting
First Posted : January 31, 2014
Last Update Posted : March 21, 2024
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Condition or disease | Intervention/treatment | Phase |
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Metastatic Breast Cancer Metastatic Prostate Cancer Bone Metastases | Drug: Denosumab (reduced dosing) Drug: Denosumab (standard dosing) | Phase 3 |
Denosumab, a monoclonal antibody against RANK-Ligand has been shown superior to zoledronic acid in delaying time to a first on-study skeletal related event (SRE) in patients with solid tumors, with no effects on disease progression or survival. Many SREs were silent compression fractures found only because of scheduled imaging. The approved dose of denosumab is 120 mg s.c. every 4 weeks (q4w). Although generally well tolerated, there is a time-dependent increase in osteonecrosis of the jaw in up to 8% of patients. Cases of fatal hypocalcaemia were observed during post marketing surveillance.
The optimal dose and schedule for denosumab is unknown. Denosumab is associated with considerable costs and may add toxicity; thus a study of de-escalation is warranted.
The aim of the trial is to test the hypothesis that the benefit of Denosumab is maintained if administered 120 mg q12w as compared to 120 mg q4w. The primary endpoint of this open-label randomized phase III non-inferiority trial is time to first on-trial symptomatic skeletal event (SSE: i.e. clinically significant pathological fracture, radiation therapy to bone, surgery to bone or spinal cord compression). With a non-inferiority margin of 1.2 for the hazard ratio, a power 80% and a type I error 5%, the total sample size is 1380. Secondary endpoints are safety, time to subsequent on-trial SSE, quality of life, health economic outcomes, and change in bone turnover markers. This study is open for international collaboration.
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 1380 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Supportive Care |
Official Title: | Prevention of Symptomatic Skeletal Events With Denosumab Administered Every 4 Weeks Versus Every 12 Weeks - A Non-Inferiority Phase III Trial |
Actual Study Start Date : | July 16, 2014 |
Estimated Primary Completion Date : | June 30, 2026 |
Estimated Study Completion Date : | December 31, 2028 |
Arm | Intervention/treatment |
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Active Comparator: Arm A (standard arm)
Denosumab 120mg (XGEVA®) sc. q4w
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Drug: Denosumab (standard dosing)
Denosumab 120mg (XGEVA®) sc. q4w
Other Name: XGEVA® |
Experimental: Arm B (reduced arm)
Denosumab 120mg (XGEVA®) sc. q4w [weeks 1, 5, 9] followed by Denosumab 120mg (XGEVA®) sc. q12w [weeks 13, 25, …]
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Drug: Denosumab (reduced dosing)
3x Denosumab 120mg (XGEVA®) sc. q4w followed by Denosumab 120mg (XGEVA®) sc. q12w
Other Name: XGEVA® |
- Time to first on-trial symptomatic skeletal event (SSE; Clinically significant pathological fracture, radiation therapy to bone, surgery to bone or spinal cord compression). [ Time Frame: at the latest 5 years after randomization. ]A SSE is defined as one of the following events: Clinically significant pathological fracture, radiation therapy to bone, surgery to bone, or spinal cord compression.
- Toxicity (focus on hypocalcaemia and osteonecrosis of the jaw) [ Time Frame: at the latest 5 years after randomization. ]
- Time to first and subsequent on-trial SSE [ Time Frame: at the latest 5 years after randomization. ]
- Quality of Life measured by FACT-G and FACT-BP [ Time Frame: at the latest 5 years after randomization. ]
- Skeletal morbidity period rate (SMPR) [ Time Frame: at the latest 5 years after randomization. ]
- Skeletal morbidity rate (SMR) [ Time Frame: at the latest 5 years after randomization. ]
- Health economic analysis [ Time Frame: at the latest 5 years after randomization. ]
- Bone turnover markers [ Time Frame: at the latest 5 years after randomization. ]
- Overall Survival (OS) [ Time Frame: at the latest 5 years after randomization. ]
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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patient has given written informed consent.
- Histologically confirmed diagnosis of breast or prostate cancer before randomization.
- Patient has metastatic breast cancer (stage IV, all subtypes allowed) or prostate cancer (stage IV) and bone metastases and is planned to receive or is receiving antineoplastic treatment.
- Patients with prostate cancer must have evidence of disease progression on continuous androgen deprivation therapy (CRPC).
- Patients must have ≥ 3 bone metastases (lytic or blastic or mixed). The lesions must be documented by radiological evaluation within 12 weeks before randomization (by X-Ray, CT scan, PET-CT, MRI scan or bone scintigraphy).
- WHO performance status 0-2
- Age ≥ 18 years.
- Corrected serum calcium ≥ 2 mmol/l and ≤ 3 mmol/l (medical treatments to obtain serum calcium levels in the normal range are allowed, as far as no denosumab is used. Maximally 1 dose of bisphosphonates in the case of hypercalcemia is allowed, if the bisphosphonate was applied at least 3 weeks before the first dose of denosumab).
- Liver transaminases not more than 1.5 x ULN or not more than 3 x ULN with liver metastases. Serum total bilirubin ≤ 1.5 x ULN (≤ 2.0 x ULN in case of known Gilbert's disease)
- Women are not breastfeeding. Women with child-bearing potential are using effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and during the 12 months thereafter. A negative pregnancy test before inclusion (within 7 days) into the trial is required for all women with child-bearing potential.
- Men agree not to father a child during participation in the trial and during 12 months thereafter.
Exclusion Criteria:
- Definite contraindication for denosumab (e.g. hypocalcaemia [Albumin-corrected serum calcium < 2.0 mmol/l]).
- History or current evidence of osteonecrosis of the jaw.
- Non-healed mucosa in oral cavity (by surgery or as a side effect of any other treatment).
- Jaw or dental conditions that require oral surgery or if surgery or invasive dental procedures are planned.
- Prior use of denosumab for bone metastases (dose 120 mg every 4 weeks) or bisphosphonates to treat bone metastases. Patients treated with denosumab or bisphosphonates against osteopenia or osteoporosis are allowed to enter the trial if the last dose was more than 28 days before randomization.
- Patients with known osteoporosis (T-score ≤ -2.5) at study entry (since fractures from osteoporosis are difficult to be discriminated from fractures through bone metastases).
- Radiotherapy or surgery to the bone within the last two weeks before randomization or planned within 6 weeks after randomization.
- Presence or history of CNS metastases or leptomeningeal disease. A MRI evaluation within 12 weeks before randomization must be performed in case of suspicious symptoms.
- Psychiatric disorder precluding understanding of information on trial related topics, giving informed consent, filling out QoL forms.
- Concurrent treatment in a clinical trial with SSE or SRE as primary endpoint.
- Known hypersensitivity to trial drug or hypersensitivity to any other component of the trial drug (e.g. fructose).
- Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information.
- Any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02051218
Study Chair: | Roger von Moos, PD MD | Kantonsspital Graubünden | |
Study Chair: | Arnoud Templeton, MD | Cantonal Hospital of St. Gallen | |
Study Chair: | Silke Gillessen, Prof | Cantonal Hospital of St. Gallen | |
Study Chair: | Andreas Müller, MD | Kantonsspital Winterthur KSW |
Responsible Party: | Swiss Group for Clinical Cancer Research |
ClinicalTrials.gov Identifier: | NCT02051218 |
Other Study ID Numbers: |
SAKK 96/12 000000685 ( Other Identifier: SNCTP ) 2014-001189-87 ( EudraCT Number ) |
First Posted: | January 31, 2014 Key Record Dates |
Last Update Posted: | March 21, 2024 |
Last Verified: | March 2024 |
Studies a U.S. FDA-regulated Drug Product: | No |
Studies a U.S. FDA-regulated Device Product: | No |
metastatic breast cancer castration resistant metastatic prostate cancer bone metastases |
Denosumab XGEVA de-escalation |
Prostatic Neoplasms Neoplasm Metastasis Neoplasms by Site Neoplasms Genital Neoplasms, Male Urogenital Neoplasms Genital Diseases, Male Genital Diseases |
Urogenital Diseases Prostatic Diseases Male Urogenital Diseases Neoplastic Processes Pathologic Processes Denosumab Bone Density Conservation Agents Physiological Effects of Drugs |